Non-ischemic cardiomyopathy, a condition in which cardiac contractile function is impaired without significant coronary artery disease, is an important cause of heart failure and sudden death but poorly understood. Alcohol abuse is considered the most common etiology of non-ischemic cardiomyopathy in the United States, but heavy drinkers rarely develop heart failure. In contrast, growing consensus in the published literature supports a primary role for cigarette smoking in the development of chronic cardiac injury. Cigarette smokers are much more likely to drink heavily than nonsmokers, and most alcoholics are dependent on nicotine. Reactive oxygen species originate from gas or tar phases of cigarette smoke, activated macrophages or neutrophils, and from endogenous sources of biological radicals including xanthine oxidase and mitochondrial respiratory chain complexes. Oxidative stress from cigarette smoke exposure causes lipid peroxidation in heart tissue, impaired energy metabolism, and reduced contractile function. Importantly, cigarette smoke stimulates robust collagen deposition in animal hearts that mimics tissue fibrosis classically associated with human cardiomyopathy. The central hypothesis of the proposed research plan is that chronic exposure to cigarette smoke triggers hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) in cardiac myocytes, which then impairs baseline function and reduces resistance to ethanol-mediated toxicity and acute ischemia-reperfusion injury. Studies will explore a mouse model of cigarette- and alcohol-associated cardiomyopathy with three specific aims. In Specific Aim One, we plan to investigate the individual and combined effects of chronic cigarette smoke exposure and heavy ethanol intake on cardiac structure and function using adult C57BL/6 mice. In Specific Aim Two, we will test the importance of PARP-1 hyperactivation as a mediator of myocardial injury induced by cigarette smoke exposure and heavy ethanol consumption. In Specific Aim Three, we plan to investigate the individual and combined effects of cigarette smoke exposure and heavy ethanol consumption on tissue resistance to acute ischemia-reperfusion injury. Protocols generate cohorts of mice with heart disease that simulates one common form of human cardiomyopathy. We predict the project will generate novel mechanistic insights, allow us to derive biomarker profiles for diagnosis of cigarette-related heart injury, and determine the utility of PARP-1 inhibitors for treatment of cardiac disease caused by drug abuse that is difficult to approach clinically. Heart disease related to cigarette smoking and heavy drinking is an important cause of illness and death throughout the world but difficult to study carefully in patients. Research proposed in this grant application will use mice to learn how cigarette smoking and heavy drinking damage heart muscle and whether a new class of safe medications known as "PARP-1 inhibitors" help hearts recover once drug abuse has ended. Information obtained in these studies will help doctors improve the diagnosis and treatment of chronic heart disease in adult patients who smoke cigarettes and drink in excess. [unreadable] [unreadable] [unreadable]